Mucinous cystic neoplasia (MCN) of the pancreas: systematic review and meta-analysis of sex differences in prevalence and malignancy risk between males and females
Original Article

Mucinous cystic neoplasia (MCN) of the pancreas: systematic review and meta-analysis of sex differences in prevalence and malignancy risk between males and females

Marcus T. T. Roalsø1,2,3#, Daniel L. Hughes4#, Patrik Larsson5,6, Poya Ghorbani5,6, Nikolaos Kartalis7,8, Carlos Fernándes Moro9,10,11, Kjetil Søreide1,3,5,12 ORCID logo

1Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway; 2Department of Quality and Health Technology, University of Stavanger, Stavanger, Norway; 3Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway; 4Department of Hepatopancreaticobiliary Surgery, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 5Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 6Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden; 7Division of Radiology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden; 8Department of Radiology, Karolinska University Hospital, Stockholm, Sweden; 9Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; 10Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden; 11Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden; 12Department of Clinical Medicine, University of Bergen, Bergen, Norway

Contributions: (I) Conception and design: K Søreide, MTT Roalsø; (II) Administrative support: K Søreide; (III) Provision of study materials or patients: MTT Roalsø, DL Hughes, P Larsson, P Ghorbani, N Kartalis, CF Moro; (IV) Collection and assembly of data: MTT Roalsø, DL Hughes, P Larsson, P Ghorbani, N Kartalis, CF Moro; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Prof. Kjetil Søreide, MD, PhD, FRCS(Edin), FACS FEBS (hon). Department of Gastrointestinal Surgery, Stavanger University Hospital, Helse Stavanger HF, Postboks 8100, 4068 Stavanger, Norway; Gastrointestinal Translational Research Unit, Stavanger University Hospital, Stavanger, Norway; Division of Surgery and Oncology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Email: ksoreide@mac.com.

Background: Among the pancreatic cystic neoplasia, the mucinous cystic neoplasia (MCN) is less-well understood as these are a much rarer to come by and a poorly described cyst entity. Notably, the MCNs have previously been thought to almost exclusively develop in females, with few reports of MCN in males. Here we present a case of male MCN together with a systematic review of the disparities in sex-dependent prevalence and malignancy risk as found in the literature.

Methods: A systematic review and meta-analysis were conducted on pre-existing literature to assess the incidence and malignancy rates of MCN in male and female patients. The study protocol was prospectively registered on PROSPERO (CRD42024606793). A comprehensive search of PubMed, Embase, MEDLINE and Web of Science was performed covering all studies published from January 2014 to August 2024.

Results: The study included 51 studies with a total of 3,519 patients. Prevalence rates show a marked predominance of MCN in female patients at 84.5% [95% confidence interval (CI): 80.5–87.9%], while malignancy rates are significantly higher in male patients with MCN 47.2% (95% CI: 26.1–69.3%) compared to females at 16.6% (95% CI: 6.4–36.6%).

Conclusions: Among all studies reporting on MCN, the systematic review of accumulated data found an overall prevalence of 14.2% in males, but with an almost 50% risk of malignancy rate in males compared to females.

Keywords: Pancreatic cysts; mucinous cyst; male; malignancy; mucinous cystic neoplasia (MCN)


Submitted Nov 22, 2024. Accepted for publication Apr 03, 2025. Published online Apr 24, 2025.

doi: 10.21037/cco-24-124


Highlight box

Key findings

• This systematic review of mucinous cystic neoplasia (MCN) in the pancreas found that, even if it is more common in female, the male rate is about 15%. The associated malignancy risk is considerably higher in men compared to female.

What is known and what is new?

• MCN is known to occur more often in female than males.

• This study demonstrates that about 14% of MCN occur in men. While MCNs are much rarer in men, the malignancy rate in men is reported to be about 3 times higher, with a pooled rate of 47.2%, in men compared to 16.6% in female.

What is the implication, and what should change now?

• Further investigation into the gender-disparities in MCN of the pancreas needs to be done, in particular to the putative molecular differences and malignancy risk associated with sex.


Introduction

Pancreatic cysts have become increasingly recognized as a clinical entity due to the overall increase and widespread in use of cross-sectional imaging in the population (1-3). Most cysts entities when detected are small in size and pose very little risk for malignancy, but some cyst types are described as premalignancies with a clear potential for invasive cancer development (2,4-6). Among the premalignant cysts are the mucinous cystic entities (4,6) (Figure 1), most commonly found as intraductal papillary mucinous neoplasia (IPMN) (3) and, considerably less common as mucinous cystic neoplasia (MCN) (7-9).

Figure 1 Overview of most common pancreatic cysts. Reproduced with minor edits and with permission from Aunan et al. (6) ©Springer 2021.

While an increasing knowledge base is developing for the more common IPMN lesions (3), there is less well-known data of MCNs as these are a much rarer to come by and hence not a well-described cyst entity overall. Many publications are still based on case reports (10-15), with larger case series being the exception rather than the rule (16-18). Notably, the MCNs have previously been thought to almost exclusively develop in females, but this has been controversial. For example, one report on MCN stated 0% in males (19), while another study suggests that up to 10% were reported to occur in males (2). In a recent, large multicenter study from Japan of 328 MCNs, only 7 (2.1%) where reported to occur in males (16). The diagnosis can be challenging (see Case presentation), as presentation in males is rare and hence often other differential diagnosis are considered as a priority initially. Findings on imaging (Figure 2) and histopathology (Figure 3) confirms the diagnosis.

Figure 2 CT or MRI of MCN in a male patient. Consecutive imaging done in a male patient at time of first detection and after 5 years with descriptive changes to CT and MRI. (A) Images of the male patient showing the 3 cm cystic lesion in the tail of the pancreas (white arrows in a-f, showing the same lesion in different phases). In CT (a,d), there are shell-like calcifications in the cyst wall (short open arrows). In the T2-weighted images (b,e), internal septations can be identified (open white arrows). There are no signs of impeded diffusion (c) or contrast enhancing mural nodules (f). (B) Images of the same patient as in (A), 5 years later, showing the cystic lesion in the tail of the pancreas has increased to 3.5 cm (white arrows in a-f). In DWI (b), there is a 5 mm foci of impeded diffusion. In two-dimensional magnetic resonance imaging cholangiopancreatography (e), the main pancreatic duct exhibits slightly variable width (white arrow). CT, computed tomography; DWI, diffusion weight imaging; MCN, mucinous cystic neoplasia; MRI, magnetic resonance imaging.
Figure 3 Histopathology of the resection specimen from a male patient with a MCN. (A) Gross sagittal section of the pancreatic tail reveals a large cyst and a smaller daughter cyst, both without communication with the main pancreatic duct. The luminal surface is smooth, lacking papillary projections. (B) Red frame: histological examination shows the cyst wall lined by a single layer of cuboidal epithelium (red arrows) with mild nuclear atypia, indicative of low-grade dysplasia. The subepithelial ovarian-type stroma (green arrowhead) contains residual pancreatic parenchyma, including a duct (blue dashed area) and an islet (yellow dashed area). Luminal side (black star). Blue frame: an area of marked regressive change is observed, with denuded epithelium and luminal macrophages (blue arrow). The cyst wall is thickened and dominated by hyaline fibrosis (blue star). Green frames: the ovarian-like stroma, composed of tightly packed spindle cells (left), shows extensive immunoreactivity for the progesterone receptor (right). Hematoxylin-eosin stain: red and green frames, 250 µm; blue frame, 500 µm. MCN, mucinous cystic neoplasia.

Of note, several reports exist to the malignancy risks and findings of MCN in females (20-22), even during pregnancy which is a gender-specific finding (10,11,21,23,24). Further, the malignancy risk is considerable, with a reported variance in high-grade dysplasia (HGD) and invasive lesions between 10% and up to 25%, also for pancreatic MCNs found in females (17,25-27). Case reports have suggested a high risk in MCNs associated with male sex (13,15,28). Due to the rarity of pancreatic MCN in males, some reports of MCN have excluded all males with MCN in order to prevent bias from misclassification when investigating large databases (20,26), and hence the findings may not apply to males when only females are investigated for the condition (20,26).

Case presentation

A previously healthy 50-year-old male was referred to the hepatobiliary-pancreatic (HPB)-department at Karolinska University Hospital. The patient had undergone a laparoscopic cholecystectomy due to abdominal pain (at another department at Karolinska) two months prior to being referred to the HPB-department. The preoperative computed tomography (CT) had shown cholelithiasis and a pancreatic cyst.

After completion of and recovery from gallbladder surgery, the pancreatic cyst was further investigated with additional CT and magnetic resonance imaging (MRI) and the patient was discussed at a multidisciplinary team conference (MDT).

The radiological investigation showed a 3 cm lobulated cyst in the pancreatic tail with shell-like calcifications in the wall and internal septations (Figure 2A). There were no signs of impeded diffusion on MRI. The cyst had no evident communication with the main pancreatic duct (MPD). The lumen of the MPD had a variable width and was 4 mm in the pancreatic body downstream of the cyst. The differential diagnosis of the cystic lesion included oligocystic serous cystic neoplasia (SCN) and side-branch IPMN (sb-IPMN); due to the elevated carbohydrate antigen 19-9 (CA 19-9) levels (50 kE/L) and the slight variation of the MPD lumen, the patient was investigated further. The clinical investigation, including gastroscopy and coloscopy, could not find any pathology explaining the elevated CA 19-9. The patient was therefore followed up with pancreatic MRI. On follow-up four months later, the serum CA 19-9 was 38 kE/L. At the MRI follow-up examination, there were no changes in the imaging findings and the patient was therefore included in annual surveillance with MRI.

Five years later, the cyst had increased in size from 3 to 3.5 cm and two approximately 5 mm foci with signs of impeded diffusion were identified on MRI (Figure 2B). The serum CA 19-9 was 57 kE/L. Based on the above-mentioned changes of the imaging findings, the MDT concluded that resection is indicated and should be discussed with the patient. At the outpatient clinic, the decision to proceed with resection of the cyst was made with the consent of the patient.

The patient underwent a minimal invasive distal pancreatectomy with splenectomy. Perioperatively, it was clear that the cyst reached into the splenic hilum and it was not possible to separate the cyst from the splenic vessels. Therefore, the spleen was resected together with the distal pancreas. The procedure was uneventful, with a per-operative bleeding of 100 mL. The pancreas was divided with staple and a passive drain was placed (in line with institutional practice at that time). The initial postoperative course was also uneventful, and the patient was discharged to a rehabilitation clinic after three days. The patient was however readmitted five days later due to fever and abdominal pain. A CT showed a fluid collection, and a new percutaneous drain was placed with pancreatic amylase level of 145 mikrokat/L indicating a pancreatic fistula. The patient had a long-standing leakage that was internalised after two months using endoscopic ultrasound assisted internal drain placement.

The pathological examination of the specimen was performed using a standardised protocol. The histological examination (Figure 3) showed a 32 mm multilocular cystic tumour lined by cubic epithelium with mild nuclear atypia. The epithelial cells exhibited eosinophilic cytoplasm, with some areas containing mucin. Furthermore, areas of regressive tissue changes were observed, characterized by denuded epithelium, infiltration of macrophages, a thickened wall with hyaline fibrosis, and focal osseous metaplasia. The underlying ovarian-type stroma consisted of densely packed spindle cells. The immunohistochemistry showed expression of oestrogen- and progesterone-receptors and positivity for smooth muscle antibodies (SMA) and Wilms tumor protein (WT1) in the ovarian-type stroma. There was sparse expression of tyrosine hydroxylase staining, highlighting luteinized stromal cells. The epithelium was positive for CA 19-9, CK7 and CK17 with minimal expression of MUC1, MUC6 and CA 125. It was negative for CDX2, mCEA, vimentin, MUC2, MUC5AC and IMP-3. The was no over-expression of p53. There was preserved expression of SMAD4 and low proliferation in Ki-67. In all, the immunohistochemistry indicated a MCN of the pancreas. The dysplasia was low-grade. There were no suggestions of malignant transformation. In total 22 regional lymph nodes were investigated with no signs of malignancy.

The final postoperative anatomical diagnosis was concluded to be a 32 mm MCN with low grade dysplasia, despite male gender. The closest margin was 1 mm from the posterior resection surface.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Objective

The aim of this article is to present an updated and systematic review on the existing knowledge of pancreatic MCN and in particular what is known about the clinical, pathological and molecular-biological description found in this particular pancreatic cyst entity. We present this article in accordance with the PRISMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-124/rc).


Methods

Study design and data sources

A systematic review and meta-analysis were conducted on pre-existing literature to assess the prevalence and malignancy rates of MCN in male and female patients. The study protocol was prospectively registered in the PROSPERO database (CRD42024606793). Study protocol can be assessed by contacting the first author.

The systematic searches of PubMed, Embase, MEDLINE and Web of Science were performed, covering all studies published from January 2014 to August 2024. The search strategy included terms such as “pancreatic cyst”, “pancreatic cystic neoplasm”, “mucinous cystadenoma”, “mucinous cystadenocarcinoma”, “men” or “male”. Boolean operators “AND” and “OR” were incorporated to broaden the search and capture relevant studies. Reference lists of relevant articles were manually searched for additional studies. Non-English articles were excluded. All search results were exported into Rayyan software (https://www.rayyan.ai) for duplicate removal and initial screening.

Inclusion and exclusion criteria

Studies were included if they met the following criteria: (I) reported the incidence or malignancy rate of MCNs in male or female patients; and (II) included patients with histologically confirmed MCNs. Studies were excluded if they met any of the following criteria: (I) studies without sex-specific data on MCN; and (II) reviews, editorials, and non-original research articles.

Data extraction and quality assessment

Two independent reviewers extracted data from each included study, with discrepancies resolved by consensus. Data extracted included the number of male and female patients, study type, study duration, number of MCN cases, and the number of cases with HGD or invasive MCN (defined as ‘malignant MCN’ for the purpose of this study) and stratified by sex. The quality of studies was assessed using the methodological index for non-randomized studies (MINORS) tool (29).

Statistical analysis

Statistical analysis was conducted using R software (version 3.6.3, R Foundation for Statistical Computing, Vienna, Austria). Pooled estimates of the incidence and malignancy rates of MCNs in male and female patients were calculated using a random-effects model incorporating the DerSimonian-Laird method in order to account for expected heterogeneity across studies. Proportions and 95% confidence intervals (CIs) were calculated for each study. Between-study heterogeneity was evaluated using the I2 statistic and Cochran’s Q test, with I2 values above 50% indicating substantial heterogeneity and values above 75% considered high heterogeneity. A P value of <0.05 was considered statistically significant.


Results

The search is shown in the study flow chart presented in Figure 4 and included 51 studies, for a total of 3,519 patients. The included studies are presented in Tables 1,2. Eleven were multicenter studies (27,31,33,36,38,40,57,58,62,73,74), and the remainder single-center studies. The MINORS score for the 12 studies (27,28,31,39,42,46-48,53,58,61,63) used to calculate sex-differences in malignancy rate (Table 2) were between 8 and 19, as presented in Table S1.

Figure 4 PRISMA diagram. IPMN, intraductal papillary mucinous neoplasia; MCN, mucinous cystic neoplasia.

Table 1

Summary of the reported prevalence of MCN based on sex within the current literature

Study Case report (Y/N) Single vs. multicentre study Number of MCN cases
Total Male Female
Agarwal A 2016 (30) N Single centre 5 3 2
Ahmad M 2020 (31) N Multicentre 492 116 376
Alkhateeb M 2020 (32) Y Single centre 1 1 0
An S 2019 (33) N Multicentre 69 1 68
Barutcuoglu B 2022 (34) N Single centre 25 9 16
Chang YT 2015 (35) N Single centre 58 2 56
Chaudhari V 2019 (36) N Multicentre 128 21 107
Chen Y 2018 (37) N Single centre 32 5 27
Chien C 2017 (38) N Multicentre 47 6 41
Choi J 2015 (39) Y Single centre 1 1 0
Chu L 2022 (40) N Multicentre 33 1 32
Dong Z 2022 (41) N Single centre 33 4 29
Ethun C 2017 (42) N Single centre 349 39 310
Fallahzadeh M 2014 (13) Y Single centre 1 1 0
Fan X 2019 (43) Y Single centre 1 1 0
Gao J 2021 (44) N Single centre 55 5 50
Gilani S 2020 (45) N Single centre 33 2 31
Griffin J 2017 (46) N Single centre 142 5 137
Gurzu S 2019 (47) N Single centre 4 2 2
Hui L 2018 (48) N Single centre 63 3 60
Hwang J 2018 (49) N Single centre 8 1 7
Jablonska B 2017 (50) N Single centre 5 1 4
Khoury T 2020 (51) N Single centre 11 4 7
Li C 2016 (52) N Single centre 19 3 16
Liang H 2021 (53) N Single centre 165 10 155
Lin X 2014 (54) N Single centre 20 6 14
Lipinski M 2018 (55) N Single centre 3 1 2
Oh H 2014 (56) N Single centre 22 3 19
Oh S 2017 (57) N Multicentre 16 5 11
Ohtsuka T 2020 (58) N Multicentre 364 7 357
Ohtsuka T 2014 (59) N Single centre 21 1 20
Paziewska A 2020 (60) N Single centre 11 2 9
Park J 2014 (61) N Single centre 90 1 89
Pezzilli R 2020 (62) N Multicentre 38 6 32
Postlewait L 2017 (27) N Multicentre 349 39 310
Revoredo-Rego F 2019 (63) N Single centre 10 1 9
Ribaldone D 2020 (64) N Single centre 31 10 21
Roch A 2017 (65) N Single centre 108 8 100
Scourtas A 2017 (66) N Single centre 136 4 132
Tamura S 2017 (67) Y Single centre 2 2 0
Tian H 2024 (68) N Single centre 93 6 87
Tomishima K 2020 (28) Y Single centre 1 1 0
Wang G 2021 (69) N Single centre 14 2 12
Wang GX 2020 (70) N Single centre 44 11 33
Xie H 2020 (71) N Single centre 31 7 24
Yang J 2019 (72) N Single centre 32 5 27
Yang Z 2022 (73) N Multicentre 205 49 156
Ye M 2023 (74) N Multicentre 26 2 24
Yuan Z 2024 (75) N Single centre 15 3 12
Zhang W 2017 (76) N Single centre 21 4 17
Zhang G 2023 (77) N Single centre 36 8 28

MCN, mucinous cystic neoplasia; N, no; Y, yes.

Table 2

Reported rate of malignancy stratified by patient sex

Study Number of male MCN cases Number of female MCN cases
Total With high grade dysplasia/malignancy Total With high grade dysplasia/malignancy
Ahmad M 2020 (31) 116 96 376 272
Choi J 2015 (39) 1 1 0 0
Ethun C 2017 (42) 39 15 310 37
Griffin J 2017 (46) 5 1 137 12
Gurzu S 2019 (47) 2 2 2 1
Hui L 2018 (48) 3 2 60 13
Liang H 2021 (53) 10 0 155 15
Ohtsuka T 2020 (58) 7 0 357 43
Park J 2014 (61) 1 0 89 9
Postlewait L 2017 (27) 39 15 310 24
Revoredo-Rego F 2019 (63) 1 1 9 1
Tomishima K 2020 (28) 1 1 0 0

MCN, mucinous cystic neoplasia.

The pooled data are presented in Figures 5-8, respectively. Prevalence estimates of MCN in male patients (Figure 5) resulted in a pooled proportion of 14.2% (95% CI: 11.3–17.84%). The prevalence estimates of MCN in female patients (presented in Figure 6) produced a pooled proportion of 84.5% (95% CI: 80.5–87.9%). The prevalence estimates of malignant MCN in male patients (n=225) gave a pooled malignancy rate of 47.2% (95% CI: 26.1–69.3%), as shown in Figure 7. The prevalence estimates of malignant MCN in female patients (n=1,805; Figure 8) resulted in a pooled malignancy rate of 16.6% (95% CI: 6.4–36.6%). Overall, the main findings are summarized in Figure 9.

Figure 5 Forest plot of pooled male MCN cases. Prevalence estimates of mucinous cystic neoplasms in male patients. Pooled proportion: 14.2% (95% CI: 11.3–17.8%). Heterogeneity: I2 =76.8%. CI, confidence interval; MCN, mucinous cystic neoplasia.
Figure 6 Forest plot of pooled female MCN cases. Prevalence estimates of mucinous cystic neoplasms in female patients. Pooled proportion: 84.5% (95% CI: 80.5–87.9%). Heterogeneity: I2 =80.2%. CI, confidence interval; MCN, mucinous cystic neoplasia.
Figure 7 Forest plot of pooled male malignant MCN cases. Prevalence estimates of malignant mucinous cystic neoplasms in male patients (n=225). Pooled malignancy rate: 47.2% (95% CI: 26.1–69.3%). Heterogeneity: I2 =78.6%. CI, confidence interval; MCN, mucinous cystic neoplasia.
Figure 8 Forest plot of pooled female malignant MCN cases. Prevalence estimates of malignant mucinous cystic neoplasms in female patients (n=1,805). Pooled malignancy rate: 16.6% (95% CI: 6.4–36.6%). Heterogeneity: I2 =98.0%. CI, confidence interval; MCN, mucinous cystic neoplasia.
Figure 9 Sex differences in prevalence and malignancy rates of MCN of the pancreas. Prevalence rates show a marked predominance of MCN in female patients (84.5%, 95% CI: 80.5–87.9%), while malignancy rates are significantly higher in male patients with MCN 47.2% (95% CI: 26.1–69.3%) compared to females (16.6%, 95% CI: 6.4–36.6%). CI, confidence interval; MCN, mucinous cystic neoplasia.

Discussion

This meta-analysis demonstrates notable sex-based differences in the prevalence and malignancy rates of MCN. MCNs were significantly more prevalent in female patients, with a pooled prevalence of 84.5% in females compared to an estimated pooled prevalence of 14.2% in males, consistent with previous observations that MCNs predominantly affect females. This sex-based disparity may be attributable to hormonal or genetic factors that promote cyst formation in female pancreatic tissue.

Despite the lower prevalence of MCNs in males, the malignancy rate among male patients was substantially higher at 47.2%, compared to 16.6% in females. These findings suggest that while rare, MCNs in male patients may exhibit a more aggressive course or may often remain undetected until later stages. However, this remains as speculative thoughts, as no robust data to support causes to the observed differences in relation to clinical or biological variation exists at this time. Clinically, the observed variation underscores the importance of vigilant evaluation and potential early intervention for pancreatic cystic lesions in males to mitigate malignancy risks. As noted by others, the misclassification risk is substantial in pancreatic cysts, even in the modern age with multiple imaging studies and endoscopic ultrasound at hand (26,78). Further research is warranted to elucidate the biological mechanisms underlying these sex-based differences and to refine sex-specific recommendations for MCN management.

Risk for malignancy in MCN has first and foremost been ascribed to size of the cyst, with cut-offs proposed at 30 mm (79) and at 40 mm (80) and some even at 50 mm (26). As for other pancreatic cysts, other worrisome features such as a mural nodule or cyst wall enhancement or thickening is often considered as indications for resection (17,80), in otherwise surgically fit patients. While MCN with malignancy tend to occur in somewhat elderly patients and with larger cyst size, size is not statistically significant between groups (likely owing to small sample size) (17). In one study, size up to 50 mm had no malignancy risk in the absence of other features, such as mural nodule or wall enhancement (26). A systematic review found only mural nodule to be predictive of presence of malignancy (81), while no other clinical or cyst features, including tumor biomarkers, were reliable in predicting malignancy (81). Compared to invasive IPMNs, malignant MCN is reported to have a better prognosis if no distant spread is found (73). Why and how MCNs degenerate into malignant transformation is not well understood.

For unknown reasons, the most common location of MCNs is in the distal pancreas (82), and more than 80–90% of resections are performed as left-sided pancreatectomies (27,82). This was also noted in the case presented in this paper, with a left-sided resection and splenectomy being performed. The practice of adding a splenectomy to a distal pancreatic resection has been highly variable in the past, with differences between hospitals (83-85). The contention in the past has been to the role of splenectomy with lymph node resection as a proper oncological procedure, at least for indications involving a suspicious risk of neoplasia or with risk for malignancy. Only recently have this routine practice been challenged, with a very low yield rate of node metastases found in the splenic hilum (86). Also, a splenectomy may often have been performed as a spleen-preserving procedure have been viewed as more difficult, particularly when done by minimal-invasive access in the past. Furthermore, the definition of a left-sided pancreatic resection has just recently been unified by consensus terminology (87), including splenectomy. When to leave the spleen and by what methods (vessel preserving or vessel-resecting) is still debated (88), as is the role of splenectomy for oncological purposes for malignancy (86,89). One study reports a higher rate of malignancy of lesions in the head (21 of 51 pancreatoduodenectomies; malignancy rate of 40%) (27), at least based on resectional series.

The role of surveillance for MCNs continues to be debated. A recent large, multicenter study from Japan found the 1-, 5-, and 10-year cumulative incidence rates of malignant MCN to be 0.8%, 5.6%, and 36.5%, respectively (16). Based on the findings they proposed that malignancy risk over time is too high to warrant surveillance, and surgery should be considered. However, a dual institution study from Italy suggest that surveillance can be entertained in most patients with size <50 mm in the absence of symptoms, mural nodule or wall enhancement, as the risk of malignancy is low (26). This is also supported by a more recent Chinese study (22), also reporting a favorable long-term survival in the few resected for malignancy, reporting 70% 5-year overall survival.

The molecular-biological differences underlying the MCNs is poorly understood. The ovarian-like stroma of the cysts and the positive staining of estrogens and progesterons, suggest a hormone-related tumorigenesis, which may explain the higher prevalence in women. However, androgens receptors are also expressed, as demonstrated by immunohistochemistry (90,91), and steroidogenesis in the ovarian-like stroma has been debated for more than a decade (92). Investigations into putative hormone expression or sexual dysfunctions of puberty have only produced very small, hypothesis-generating data (93). The most convincing data related to hormone-influence comes from the observed cases during pregnancy, with an overall younger age (around 30 years) and larger tumor size (over 10 cm) and reported growth spurt of the cyst during pregnancy (21,24).

Investigations into the mechanisms of neoplasia, has suggested activation of Wnt-signalling in the stroma (by means of beta-catenin staining) associated with MCN (94). Others have found mutations in ring finger protein 43 (RNF43) associated with cytological atypia in the ovarian-like stroma, and a high prevalence of KRAS mutations with increasing dysplasia and all with invasive cancer (92,95). Gradual telomere shortening has been found as a feature in MCN tumorigenesis (19). Several other molecular features of low- to high-grade dysplasia are found along the route of other premalignant mucinous lesions in the pancreas (96,97).

Some limitations should be mentioned. As noted, most data are accrued from case series, case reports and retrospective institutional series. Only more recently has multicenter reports emerged. Despite this, we believe the findings are robust and updated, based on the most recent available literature. The study may serve as a backdrop for further research into the genesis of MCN as a rather rare but a particular cyst of interest in the pancreas.


Conclusions

The prevalence of MCN in males is 14.2% in case series of surgical resections, which is a higher rate than previously reported. Of note, there is a much higher malignancy rate in males, almost 3 times that of females, with an unexplained biological rationale for the increased risk, but drivers in sex hormone-related pathways may be further interrogated.


Acknowledgments

None.


Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-124/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-124/prf

Funding: This work was supported in part by HelseVest grant (#F-12652) to K.S.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-124/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments.. Written informed consent was obtained from the patient for the publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


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Cite this article as: Roalsø MTT, Hughes DL, Larsson P, Ghorbani P, Kartalis N, Moro CF, Søreide K. Mucinous cystic neoplasia (MCN) of the pancreas: systematic review and meta-analysis of sex differences in prevalence and malignancy risk between males and females. Chin Clin Oncol 2025;14(2):19. doi: 10.21037/cco-24-124

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